1-oxo-substituted-tetrahydronaphthalenes (substituted-tetralones)

ABSTRACT

COMPOUNDS OF THE FORMULA ARE DISCLOSED:   2-R1,R2,R3,R4-1,2,3,4-TETRAHYDRONAPHTHAN-1-ONE   WHEREIN R1 IS HYDROGEN, HYDROXYMETHYLENE, BENXYLIDENE OR BENZYLIDENE SUBSTITUTED BY HALOGEN OR NITRO; R2, R3 AND R4 ARE HYDROGEN, ALKYL, ALKOXY, AMINO, ACYLAMINO, CARBOXY, CARBOXYALKYL, HALOGEN, HYDROXY, NITRO, ALLYL AND METHANESULFONYLAMINO. THESE COMPOUNDS ARE USEFUL IN PROVIDING SYMPTOMATIC RELIEF IN ALLERGIC CONDITIONS SUCH AS ASTHMA, HAY FEVER AND THE LIKE.

United States Patent US. Cl. 260-590 9 Claims ABSTRACT OF THE DISCLOSURECompounds of the formula are disclosed:

wherein R is hydrogen, hydroxymethylene, benzylidene or benzylidenesubstituted by halogen or nitro; R R and R are hydrogen, alkyl, alkoxy,amino, acylamino, carboxy, carboxyalkyl, halogen, hydroxy, nitro, allyland methanesulfonylamino. These compounds are useful in providingsymptomatic relief in allergic conditions such as asthma, hay fever andthe like.

The present invention is concerned withl-oxo-substituted-tetrahydronaphthalenes (substituted-tetralones) havingthe following structural formula:

wherein R is hydrogen, hydroxymethylene, benzylidene or benzylidenesubstituted by halogen or nitro; R R and R are hydrogen, alkyl, alkoxy,amino, acylamino, carboxy, carboxyalkyl, halogen, hydroxy, nitro, allylor methanesulfonylamino. The R R substituents are preferably substitutedat the 5,6,7 or 8 position of the 3,4-dihydro-1 (2H)-naphthalenonenucleus.

In the above definitions for R R and R the term alkyl and the alkylportion in terms such as alkoxy and carboxyalkyl is meant to encompassstraight or branched chain alkyl groups having 1-6 carbon atoms. Theseinclude, for example, methyl, ethyl, propyl and the like.

The acyl portion of acylamino is meant to be the residue derived from analkanoic acid such as acetic, propionic, butyric and the like.

The term halogen includes all its four members, preferably chlorine.

These compounds form salts with pharmaceutically acceptable acids andbases. For example, they form acid addition salts with acids such ashydrochloric, sulfuric, nitric and the like and they form base additionsalts with bases such as sodium hydroxide, potassium hydroxide and thelike. These salts are also Within the scope of this invention.

The above compounds exhibit anti-allergic activity in a mammalian host,e.g., cats, dogs, monkeys and the like. For example, these compounds arecapable of protecting guinea pigs from histamine-induced reactions at adose of 1 mg. to 100 mg./kg. orally or by injection.

The compounds of this invention are useful in alleviat ing or inproviding symptomatic relief in allergic reactions such as hay fever,asthma, eczema and dermatitis. Generally speaking, a dose of 1 mg. to100 mg./kg. of body 3,833,726- Patented Sept. 3, 1974 weight of theanimal being treated orally or parenterally is required to achieveanti-allergic action.

In order to use these compounds they are combined with pharmaceuticalexcipients such as lactose, mannitol and compressed into dosage formssuch as tablets.

They can also be combined with parenteral vehicles such as water forinjection, peanut oil or into dosage forms for parenteraladministration.

According to this invention, these compounds are pre- 0 pared asfollows. First, an appropriate substituted phenylhydrogen succinate issubjected to a Fries rearrangement. The resulting18-(substituted-2-hydroxybenzoyl)propionic acid is methylated, usingstandard methylating agents such as dimethylsulfate. The methylatedcompound is subsequently reduced to the correspondingv-(2-methoxyphenyl)butyric acid. Ring closure to the substitutedS-methoxytetralone is accomplished with condensing agents such aspolyphosphoric acid, phosphorous oxychloride and the like.Alternatively, ring closure is effected by treating the acid chloridewith aluminum chloride. Ether cleavage is accomplished either byrefluxing the ether in a mixture of aluminum chloride and benzene or byfusion in pyridine hydrochloride.

The foregoing reaction is illustrated as follows:

H OH (I? O CCHzCHaC O OH cmcmooon OCH:

CHzCHzC O OH OCHe CHzCHzCHzCO OH OCH: OH m X H X The 6-allyl-5-hydroxytetralone is obtained by the fol lowing illustrated Claisenrearrangement:

HO H 1 10:

OH H(\) @4510: U l l O O N OH OH (:GNH:

(H) |OI NHSOzCI-Ia In order to further illustrate the practice of thisinvention, the following examples are included:

EXAMPLE 1 1,5 Dihydroxy 6-nitro-1,2,3,4,-tetrahydronaphthalene and1,5-Dihydroxy-8-nitro-1,2,3,4-tetrahydronaphthalene.To a solution of76.5 g. (467 mmol) of 1,5-dihydroxy-1,2,3, l-tetraliydronaphthalene in750 ml. of glacial AcOH, H 0 (150 ml.) was added and the solution wascooled to 0 before 70% HNO (59.0 ml.) was added. The HNO was addedslowly maintaining a reaction temperature below 15. After 30 min., thereaction mixture was poured onto 5 l. ice-H O and extracted with CHCl(2X 1.) and CH Cl (1X 1.). An insoluble solid was collected byfiltration and 10.4 g. (10.7%), m.p. 179-184 of homogeneous solid wasobtained. The combined organic extracts were dried (MgSO and evaporatedin vacuo to give 74.2 g. (76.1%) of a brown, oily residue. This crudemixture of products was placed on an acid washed A1 0 column (1 kg.) andeluted with CHCl MeOI-I fractions of 500 ml. Homogeneous 6 isomer wasobtained from 1% MeOHCHCl eluate; yield 26.4 g. (27.0%). Analyticallypure sample was obtained by recrystallization from EtOAc-hexane, m.p.98-100".

Anal.Calcd. for C H NO C, 57.41; H, 5.30; N, 6.70. Found: C, 57.57; H,5.42; N, 6.44.

The 8-isomeric product was obtained from the MeOH chute and gave a totalyield of 12.3 g. (13.0%), m.p. 179-184 when combined with solidrecovered from the extraction. The analytical sample was obtained byrecrystallization from MeOH- H 0, m.p. 183-185".

Anal.Calcd. for C H NO C, 57.41; H, 5.30; N, 6.70. Found: C, 57.52; H,5.42; N, 6.85.

EXAMPLE 2 3,4 Dihydro 5 hydroxy-6-nitro-1(2H)-naphthalenone-To anacetone solution (250 ml.) containing 28.5 g. (136 mmol) of6-nitro-1,5-dihydroxy-Tetralin, a mixture of 15.0 g. (150 mmol) of CrOin H 0 (50 ml.) and H SO (16.5 ml.) was added in a dropwise manner below10. The reaction was allowed to stir at 0 for 30 min. and poured ontoice-H O (2 1.). The solid which formed was collected by filtration,yield 26.3 g. (93.6%), mp. 127-428". The analytical sample was obtainedby recrystallization from EtOAc-hexane, m.p. 130-131.

Anal.Calcd. for C H NO C, 57.97; H, 4.38; N, 6.76. Found: C, 58.05; H,4.56; N, 6.50.

EXAMPLE 3 3,4 Dihydro 5 hydroxy-S-nitro-l(2H)-naphthalenone.-A coldmixture of 3.30 g. (33.0 mmoles) of CrO H 50 (3.7 ml.) and H 0 (12.5ml.) was added dropwise to an acetone solution (100 ml.) of 5.78 g.(27.5 mmoles) of 8-nitro-1,5dihydroxy-Tetralin maintained below 10. Thereaction mixture was stirred at 0 for an additional 30 min. before beingpoured onto 1 l. of ice-H O. The resultant solid was collected to give4.42 g. (77.4%), m.p. 250-251 dec. The analytical sample was obtained byrecrystallization from EtOAc-hexane, m.p. 254 dec.

Anal.-Calcd. of C H NO C, 57.97; H, 4.38; N, 6.76. Found: C, 58.01; H,4.46; N, 6.90.

EXAMPLE 4 6-Amino 3,4 dihydro-5-hydroxy-1(2H)-naphthalenoneHydrochloride.-A suspension of 2.07 g. (10.0 mmol) of6-nitro-5-hydr0xytetralone in MeOH ml.) was hydrogenated over 100 mg. ofPt0 until the theoretical uptake of hydrogen was observed. The catalystwas removed by filtration after 10 ml. of 6N HCl had been added to thereaction mixture. The MeOH filtrate was evaporated and a solid productwas obtained. The solid residue was recrystallized from 2-PrOH-MeOH andgave the analytically pure product; yield 1.15 g. (54.0%), m.p. 226-230dec.

Anal.Calcd. for C H NO -Hclz C, 56.21; H, 5.66; N, 6.56; Cl, 16.59.Found: C, 56.36; H, 5.83; N, 6.80; Cl, 16.47.

EXAMPLE 5 S-Amino 3,4 dihydro-5-hydroxy1(2H)-naphthalenoneHydrochloride.A MeOH solution (200 ml.) containing 1.04 g. (5.02 mmol)of 8-nitro-5hydr0xytetralone was hydrogenated over PtO (100 mg.) untilthe theoretical uptake of hydrogen had occurred. After 10 ml. of 6N HClhad been added to the reaction mixture, the catalyst was removed byfiltration and evaporation of the MeOH filtrate gave the crude solidresidue; yield 953 mg. (88.0%), m.p. 204212 dec. Recrystallization ofthe crude material from 2-PrOH gave the analytical yellow salt, m.p.211213 dec.

Anal.-Calcd. for C H NO -HClz C, 56.21; H, 5.66; N, 6.56; Cl, 16.59.Found: C, 56.51; H, 5.77; N, 6.80; Cl, 16.72.

EXAMPLE 6 S-Hydroxy 6 [N,N-dimethanesulfonyl]aminotetralone.A mixture ofCH Cl (500 ml.), 100 ml. of triethylamine, 21.4 g. (100 mmoles) of5-hydroxy-6-aminotetralone and 20 ml. (256 mmoles) of methanesulfonylchloride was heated at reflux for 2 hrs. The mixture was washed with H 0(1 X 500 ml.) and dried (MgSO' before being evaporated to give theN,O-trirnethylsulfonyl intermediate. The intermediate was then heated atreflux for 1 hr. in a mixture of MeOH (250 ml.) and 5% NaOH (250 ml.).The basic mixture was poured onto ice and acidified with 3N HCl. Theprecipitate which formed was collected by filtration to give aquantitative yield of the desired product, mp. 175-180". The analyticalsample was obtained by recrystallization from 2-propanol; yield 12.0 g.(47.1%), m.p.184186.

Anal.-Calcd. for C H NO S C, 43.23; H, 4.54; N, 4.20; S, 19.24. Found:C, 43.23; H, 4.66; N, 4.23; S, 19.17.

EXAMPLE 7 6-Acetamido 5 hydroxy-1-tetralone.To a suspension of 5.14 g.(24.1 mmoles) of 6-amino-5-hydroxy-1- tetralone hydrochloride in CH Cl(100 ml.) was added Et N (140 mmoles) and acetyl chloride (70 mmoles).The mixture was heated at reflux for 1 hr., extracted with 6N HCl (1X100 ml.), 5% NaHCO (1X 100 ml.), H O (1X 100 ml.) and dried with MgSO,before being evaporated to give the 5-acetoxy-6-acetamidotetraloneintermediate.

The desired product was obtained by heating the diacetyl intermediate ina mixture of MeOH (50 ml.) and 20% NaOH (50 ml.) for 1 hr. The reactionmixture was cooled, acidified and extracted with CHgCl The CH Cl extractwas dried (MgSO and evaporated to give the 6acetamido-5-hydroxytetralone; yield 4.98 g. (94% rn.p. 130-140. Theanalytical sample was obtained by recrystallization from toluene, mp.146-147 AnaL-Calcd. for C H NO C, 65.74; H, 5.98; N, 6.39. Found: C,65.69; H, 5.97; N, 6.54.

EXAMPLE 8 S-Hydroxy 8 methanesulfonamido-1-tetr-alone.To a suspension of4.27 g. (20 mmoles) of 5-hydroxy-8- amino-l-tetralone hydrochloride in100 ml. of CH Cl was added 180 mmoles of triethylamine and 100 mmoles ofmethanesulfonyl chloride. The resultant mixture was refluxed for 2 hrs.The reaction mixture was extracted with 6N HCl (2x 100 ml.), 5% NaHCOsolution (1 X 100 ml.) and H (1X 100 ml.). The CH CI solution was dried(MgSO and evaporated to give the 5,8- dimethanesulfonyl intermediate.

The desired S-hydroxy-8-methanesulfonamidotetralone was obtained byheating the 5,8-dimethanesulfonyl intermediate in a mixture of MeOH (50ml.) and 10% NaOH (50 ml.) for 1% hrs. The reaction mixture was pouredonto ice-H O and acidified giving 3.23 g. (63.4%) of solid product, mp.195-200". The analytical sample was obtained from 2-PrOH, mp. 203-205.

Anal.Calcd. for C H NO S: C, 51.75; H, 5.13; N, 5.49; S, 12.56. Found:C, 51.92; H, 5.34; N, 5.61; S, 12.71, 12.81. EXAMPLE 9.

6,8-Dinitro--hydroxytetralone.--To 1.62 g. (10.0 mmoles) ofS-hydroxytetralone in 11.2 ml. of glacial acid heated at 50, was added2.4 ml. (40.0 mmoles) of 70% HNO The mixture was stirred at 50 for 1 hr.Cooling and addition of water (50 ml.) gave crude solid product; yield2.0 g. (79.4%). The analytical sample was obtained from ethyl acetate byrecrystallization; yield 1.55 g. (61.5%), m.p. 238-239".

Anal.CalCd. for CmHgNgOsi C, H, N, 11.11. Found: C, 47.61; H, 3.24; N,11.26.

EXAMPLE l0 6-Allyl 3,4 dihydro 5 hydroxy-1(2H)-naphthalenon.-Allylbromide (17.0 g., 140 mmol), anhydrous K CO (19.3 g., 140 mmol) and5-hydroxy-1-tetralone (20.0 g., 124 mmol) was refluxed for 21 hr. in dryMe CO. The reaction mixture was evaporated in vacuo and gave a residuewhich was dissolved in EtOAc (400 ml.). After washing the EtOAc solutionwith 5% NaOH (2X 400 ml.) and H 0 (1X 400 ml.), the EtOAc was 6 driedwith MgSO, before being evaporated to give the crude5-allyloxytetralor1e; yield 24.6 g. (97.5%).

The crude 5-allyloxytetralone (12.6 g., 61.8 mmol) was heated at refluxin diethylaniline (50 ml.) for 28 hr. The reaction mixture was pouredinto 20% NaOH (1 1.) and extracted with Et O (3 XL). The basic phase wasacidified with HCl and extracted with CHCl (3X 1.5 1.). The CHClextracts were combined, dried (MgSO and evaporated to give 7.20 g.(57.2%) of crude 21 which crystallized upon standing. The analyticalsample was obtained by recrystallization from phCH -hexane, m.p. -83.

Anal.Calcd. for C H O C, 77.20; H, 6.98. Found: C, 77.25; H, 7.04.

EXAMPLE 11 2-Benzylidene 3,4 dihydro-S-hydroxy-l(2H)-naphthalenone.-Amixture of 19.4 g. (120 mmol) of 5-hydroxytetralone 12.0 g. (300 mmol)of NaOH and 14.8 g. (140 mmol) of benzaldehyde was heated at reflux for2 hrs. in 50% aqueous MeOH ml.). The mixture was allowed to stir at roomtemperature overnight. The reaction mixture was acidified with 30 ml. ofcone. HCl and poured onto ice-H O (500 ml.) giving the solid product;yield 26.1 g. (87.3%). The tan analytically pure product was obtained byrecrystallization from EtOAc-hexane; yield 12.0 g. (40.0%), m.p. 168171dec.

Anal.--Calcd. for C H O C, 81.58; H, 5.64. Found: C, 81.38; H, 5.67.

EXAMPLE 12 2-(p-Chlorobenzylidene) 3,4 dihydro 5 hydroxy-1(2H)-naphthalenone.-Using the procedure outlined in the synthesis of2-benzylidene-S-hydroxytetralone, a crude yield of 31.6 g. (92.2%), mp.217-220" was obtained from 19.4 g. mmol) of 5-hydroxytetralone and mmolof p-chlorobenzaldehyde. One recrystallization from MeOH-Et O gave theanalytical sample, mp. 229- 231.

Anal.-Calcd. for C H ClO C, 71.71; H, 4.60; CI, 12.45. Found: C, 71.87;H, 4.64; Cl, 12.19.

EXAMPLE 13 5 Hydroxy-2-(p-nitrobenzylidene)tetralone.A reaction mixturecontaining 6.51 g. (40.2 mmol) of 5-hydroxytetral-one 7.56 g. (50.0mmol) of p-nitrobenzaldehyde, 10 m1. of cone. H 80, and 50 ml. ofglacial HOAc was allowed to react at room temperature for 72 hrs. Themixture was poured onto 500 ml. of ice-H O and 11.9 g. (100%) of2-(p-nitrobenzylidene) 5 hydroxytetralone was obtained, m.p. 230-240.

EXAMPLE 14 8-Chloro-S-hydroxytetralone.-Pyridine HCl (100 g.) was heatedat 190 for 0.5 hr. and 20.0 g. (91.2 mmol) of8-chloro-5-n1ethoxytetralone was added. The reaction temperature wasmaintained at -190" for 2.5 hrs. and then poured into H 0 (1500 ml.).The precipitate which formed was collected by filtration and gave 18.2g. (97.8%) of homogeneous product, m.p. 225228. The analytical samplewas obtained by recrystallization from toluene, m.p. 229-231.

Anal.Ca1Cd. for C H ClO C, 61.08; H, 4.61; CI, 18.03. Found: C, 61.14;H, 4.78; Cl, 18.05, 17.84.

EXAMPLE l5 6 Chloro 3,4 dihydro 5 hydroxy-1(2H)-naphthalenone.A solutionof 8.28 g. (120 mmol) of NaNO in 100 ml. of cold H O was added dropwiseover 30 min. to a cooled suspension of 21.3 g. (100 mmol) of 6-amino-5-hydroxytetralone in 100 ml. of 6N HCl. The reaction mixture wasstirred at 0 for 15 min. and a solution of 11.9 g. (60.0 mmol) of Cu Clin 100 ml. of 6N HCl was added dropwise. After the evolution of N gashad ceased,

the reaction mixture was heated to boiling for 30 min. Cooling gave asolid which was collected by filtration to give 167 g. (84.8%), m.p.95-110 of crude 36. The crude 36 was sublimed at 120/2 min. and 7.40 g.(37.6%), m.p. 128-133 of the purified product was collected. Theanalytical sample wa obtained by recrystallization from hexane, m.p.133-135.

Anal.Calcd. for C H ClO C, 61.08; H, 4.61; Cl, 18.03. Found: C, 61.38;H, 4.68; Cl, 18.01.

EXAMPLE 16 3,4 Dihydro-S-hydroxy 8 methyl-1(2H)-naphthalenone.A mixtureof freshly fused pyridine hydrochloride (5.00 g.) and 2.00 g. (10.5mmol) of 3,4-dihyd1'0- 5 methoxy 8 methyl-1(2H)naphthalenone was heatedat 195-200 for 1.5 hr. Upon cooling the mixture, the material was pouredonto 50 ml. of ice-H O and the solid which formed was collected byfiltration; yield 1.79 g. (96.6%), m.p. 181-185 One recrystallization ofthe solid from PhCH gave the analytical sample, m.p. 188-190".

Anal.Calcd. for C H O C, 74.98; H, 6.86. Found: C, 75.25; H, 6.96.

References 1. A. M. El-Abbady, F. G. Baddar, and A. Labib, J.

Chem. Soc., 1960, 3420.

2. I. W. Huffman, J. Org. Chem., 24, 1759 (1959).

3. D. Papa, E. Schwenk and H. Breiger, J. Org. Chem.,

4. W. F. Newhall, S. A. Harris, F. W. Holly, E. L. Johnston, J. W.Richter, E. Walton, A. N. Wilson and K. Falkers, J. Am. Chem. Soc., 77,5646 (1955).

5. N. L. Allinger and E. S. Jones, J. Org. Chem., 27,

6. I. v. Braun, Justus Liebigs Ami. Chem., 451, 1 (1927).

7. M. A. Tobias, J. Org. Chem., 35, 267 (1970).

8. K. V. Auwers and Chr. Wiegand, J. Prakt. Chem., 134,

9. Purchased from the Aldrich Chemical Company, Cedar Knolls, NJ.

The reference numerals 1 through 9 are sources of starting material orthe method of their preparation in the examples.

We claim:

1. A compound which is 3,4-dihydro-S-hydroxy-G-nitro- 1 (2H-naphthalenone.

2. A compound which is3,4-dihydro-5-hydroxy-8-mitro-1(2H)-naphthalenone.

3. A compound which is 6,8 dini-tro 5 hydroxy 1- tetralone.

4. A compound which is 6-allyl-3,4-dihydro-5-hydroxy- 1 (2H-naphthalenone.

5. A compound which is 2-benzylidene-3,4-clihydro-5- hydroxy-l (2H-naphthalenone.

6. A compound which is 2-(p-chlorobenzylidene)-3,4 dihydro-S -hydroXy-12H) -naphthalenone.

7. A compound which is 5-hydroxy-2-(p-nitrobenzylidene) -1-tetralone.

8. A compound which is 8-chloro 5 hydroxy-itetralone.

9. A compound which is 6 chloro-3,4-dihydro-5-hydroxy-l (2H)-naphthalenone.

References Cited UNITED STATES PATENTS 2,475,718 7/1949 Papa et al.260-590 2,669,586 2/ 1954 Middleton 260590 3,506,653 4/1970 Fried260-590 3,478,106 11/1969 Hughes et a]. -1 260-590 FOREIGN PATENTS949,295 2/1964 Great Britain 260590 397,150 6/1924 Germany 260-590 OTHERREFERENCES Cromwell et al.: J. Am. Chem. Soc. 81, 4294, 4295 (1959).

Cocker et al.: Chem. Abstracts 41, 5498 (1947).

Cocker et al.: Chem. Abstracts 45, 1085 (1951).

Momose et al.: Chem. Abstracts 51, 26823 (1951).

DANIEL D. HORWITZ, Primary Examiner US. Cl. X.R.

260-485 H, 485 J, 519, 520, 556 A, 562 A, 575, 645, 469, 472, 473 F;424324, 330, 331

